Chronic Epstein-Barr Virus Infection Research Articles

The MHV68 M2 protein drives IL-10 dependent B cell proliferation and differentiation.

Murine gammaherpesvirus 68 (MHV68) establishes long-term latency in memory B cells similar to the human gammaherpesvirus Epstein Barr Virus (EBV). EBV encodes an interleukin-10 (IL-10) homolog and modulates cellular IL-10 expression; however, the role of IL-10 in the establishment and/or maintenance of chronic EBV infection remains unclear. Notably, MHV68 does not encode an IL-10 homolog, but virus infection has been shown to result in elevated serum IL-10 levels in wild-type mice, and IL-10 deficiency results in decreased establishment of virus latency. Here we show that a unique MHV68 latency-associated gene product, the M2 protein, is required for the elevated serum IL-10 levels observed at 2 weeks post-infection. Furthermore, M2 protein expression in primary murine B cells drives high level IL-10 expression along with increased secretion of IL-2, IL-6, and MIP-1α. M2 expression was also shown to significantly augment LPS driven survival and proliferation of primary murine B cells. The latter was dependent on IL-10 expression as demonstrated by the failure of IL10−/− B cells to proliferate in response to M2 protein expression and rescue of M2-associated proliferation by addition of recombinant murine IL-10. M2 protein expression in primary B cells also led to upregulated surface expression of the high affinity IL-2 receptor (CD25) and the activation marker GL7, along with down-regulated surface expression of B220, MHC II, and sIgD. The cells retained CD19 and sIgG expression, suggesting differentiation to a pre-plasma memory B cell phenotype. These observations are consistent with previous analyses of M2-null MHV68 mutants that have suggested a role for the M2 protein in expansion and differentiation of MHV68 latently infected B cells—perhaps facilitating the establishment of virus latency in memory B cells. Thus, while the M2 protein is unique to MHV68, analysis of M2 function has revealed an important role for IL-10 in MHV68 pathogenesis—identifying a strategy that appears to be conserved between at least EBV and MHV68.

Peripheral T-Cell Lymphomas: An Historical Perspective

Peripheral T-cell lymphomas (PTCL) remain largely unexplored due to disease rarity and biological heterogeneity as well as relatively recent recognition in modern classification systems. Before 1970, classifications of non-Hodgkin’s lymphomas (NHL) were based on morphology. The discovery of distinct T-, B- and natural killer (NK)–cell lineages led to two immunologically based classification systems proposed in 1974: the European Kiel and the North American Lukes-Collins. In 1982, the Working Formulation (WF), based on clinical and morphologic criteria, was developed in the United States. The updated Kiel classification separated B- and Tcell lymphomas but still failed to address some disease types. The addition of molecular genetic features/criteria and increasing immunophenotypic subclassification allowed for more diagnostic standardization and reproducibility. The International Lymphoma Study Group (ILSG) integrated morphologic, phenotypic, molecular and clinical information in the 1994 REAL (Revised European American Lymphoma) classification. The T-cell lymphomas were grouped into “precursor” neoplasms versus “peripheral” or post-thymic T-cell and NK neoplasms, the so-called “PTCLs.” The World Health Organization (WHO) subsequently made the following modifications: PTCLs were subdivided into predominantly leukemic, extranodal and nodal types; cutaneous and systemic anaplastic large cell lymphomas (ALCL) were separated; terminology was updated for some diseases; and subcutaneous panniculitis-type and hepatosplenic γδ T-cell lymphomas were recognized as distinct entities. Almost a decade later, the recently published fourth edition of the WHO classification has refined the classification further, including defining ALK-negative ALCL as a provisional entity, confining subcutaneous panniculitislike T-cell lymphoma to cases with an αβ phenotype and combining the γδ cases with primary cutaneous γδ PTCL. Two other provisional categories have been established under the category of primary cutaneous peripheral T-cell lymphomas: primary cutaneous CD4-positive small/medium-sized pleomorphic T-cell lymphoma and CD8-positive cytotoxic T-cell lymphoma. Several important advances in the pathobiology of PTCL have been made. Unlike mature B-cell lymphomas, there are virtually no recurrent translocations characterizing the PTCLs. The one exception is a proportion of ALCL cases in which a non-random t(2;5)(p23;q35) translocation produces a novel fusion protein composed of the nucleophosmin (NPM) and anaplastic lymphoma (ALK) coding regions. The use of more detailed cytogenetic analysis with comparative genomic hybridization and gene expression profiling now provide evidence for recurrent genetic changes in other PTCL subtypes. Several PTCL subtypes have viral associations that may be involved in disease pathogenesis. In 1982, HTLV1 was found to be the etiologic agent of adult T-cell leukemia and lymphoma. In 1988, T-cell lymphomas were described in patients with chronic Epstein-Barr virus (EBV) infections, and EBV was subsequently found to be associated with extranodal NK/T-cell lymphoma, nasal type and angioimmunoblastic T-cell lymphoma. With the development of molecular techniques in the 1990s, the importance of the γδ T-cell receptor rearrangement and impact on prognosis is apparent. For example, in the updated WHO classification primary cutaneous γδ T-cell lymphoma is recognized by an aggressive course and considered a new provisional entity. Although significant progress has been made in defining specific disease categories within the diverse group of PTCLs and establishing the prognostic significance, advances in therapy have been much slower. In the last several years, attention has turned to testing new chemotherapy combinations, targeted agents and high-dose chemotherapy approaches specifically in PTCL. The hope for the future is that treatment can be tailored better for PTCL and outcomes will more approximate what is observed in aggressive B-cell NHL.

The Spectrum of Epstein-Barr Virus-Associated Lymphoproliferative Disease in Korea: Incidence of Disease Entities by Age Groups

This study is to identify the spectrum of Epstein-Barr virus (EBV)-positive lymphoproliferative diseases (LPD) and relationships between these diseases in Korea. The EBV status and clinicopathology of 764 patients, including acute EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH), chronic active EBV (CAEBV) infections, B-LPD arising in chronic latent EBV infection, T & natural killer (NK) cell non-Hodgkin's lymphomas (NHL), B-NHLs, and Hodgkin's lymphomas (HD), were analyzed. T or NK cell NHLs were the most common forms of EBV-positive NHLs (107/167, 64%); among these, nasal-type NK/T cell lymphomas were the most common (89/107, 83%). According to the age, Burkitt's lymphoma was the most common in early childhood; in teenagers, chronic (active) EBV infection-associated LPD was the most common type. The incidence of NK/T cell lymphoma began to increase from the twenties and formed the major type of EBV-associated tumor throughout life. Diffuse large B cell lymphoma formed the major type in the sixties and seventies. In conclusion, primary infections in early childhood are complicated by the development of CAEBV infections that are main predisposing factors for EBV-associated T or NK cell malignancies in young adults. In old patients, decreased immunity associated with old age and environmental cofactors may provoke the development of peripheral T cell lymphoma, unspecified, and diffuse large B cell lymphoma.

Hydroa vacciniforme‐like Epstein‐Barr virus‐associated monoclonal T‐lymphoproliferative disorder in a child

Hydroa vacciniforme (HV) is a chronic photosensitivity disorder induced by ultraviolet radiation. Hydroa vacciniforme-like lymphoma is a rare cutaneous T-cell lymphoma occurring mainly in childhood. Recent studies have demonstrated an association between chronic latent Epstein-Barr virus (EBV) infection and both the benign skin disorder and the lymphoma. The authors report a 6-year-old boy with chronic EBV infection, HV-like skin eruptions, and chronic hepatitis. Histopathologic examination of a skin biopsy specimen demonstrated epidermal ballooning degeneration and dense superficial and deep perivascular and periappendageal lymphoid cell infiltrates extending to the fat lobules. Some blood vessels in the deep plexus were infiltrated by predominantly CD4+ and TIA-1+ cytotoxic T cells. The EBV genomes were found within tissue from three skin biopsies and peripheral blood cells. Monoclonal T-cell receptor gene rearrangement was present in skin biopsy specimens. Although no lymphoma has been found during 2 years of follow-up treatment, the possibility of lymphoma developing out of the current smoldering stage is of concern. The clinical manifestations of lymphoproliferative disorder and chronic active EBV infection are discussed.

The Mechanisms of Immune Escape in Chronic Active Epstein-Barr Virus Infection

慢性活动性EB病毒感染是EB病毒相关疾病中的一种较少见类型,其发病既有病毒方面的因素,亦有机体免疫功能方面的因素.EB病毒感染T细胞或自然杀伤细胞导致的克隆性扩增在发病中起关键作用,但机制尚不十分明确.EB病毒有其特殊的策略逃避免疫监视,EB病毒基因编码产物(如EBNA-1、LMP1、LMP2、EBNA-2)与宿主基因表达产物(如白细胞介素-10、转化生长因子-β、CD40-CD40配体)都参与了EB病毒的免疫逃逸.根据其免疫逃逸原理选择新的治疗方法将是今后的研究重点。

IFN-α–Stimulated Genes and Epstein-Barr Virus Gene Expression Distinguish WHO Type II and III Nasopharyngeal Carcinomas

Nonkeratinizing nasopharyngeal carcinoma (NPC) is 100% associated with Epstein-Barr Virus (EBV) and divided into two subtypes (WHO types II and III) based on histology. We tested whether these subtypes can be distinguished at the molecular genetic level using an algorithm that analyzes sets of related genes (gene set enrichment analysis). We found that a class of IFN-stimulated genes (ISG), frequently associated with the antiviral response, was significantly activated in type III versus type II NPC. Consistent with this, replication of the endogenous EBV was suppressed in type III. A strong association was also seen with a subset of ISGs previously identified in systemic lupus erythematosus, another disease in which 'normal' EBV biology is deregulated, suggesting that this pattern of ISG expression may be linked to the increased EBV activity in both diseases. In contrast, unsupervised hierarchical clustering of the complete expression profiles failed to distinguish the two subsets. These results suggest that type II and III NPC have not originated from obviously distinct epithelial precursors; rather, the histologic differences may be a consequence of a differential antiviral response, involving IFNs, to chronic EBV infection.

EXTRANODAL TYPE T/NK-CELL LYMPHOMA WITH AN ATYPICAL CLINICAL PRESENTATION

Peripheral-type natural killer (NK)-or T-cell lymphomas are rare disorders characterized with clonal proliferation of mature lymphocytes. They have been linked to chronic and active Epstein-Barr virus infection (CAEBV), which itself is not defined as a malignant hematological disorder. The authors present a patient with T/NK-cell lymphoma involving skin, kidneys, spleen, pancreas, and meninges. She was remarkable for having the mosaic feature of more than one type of extranodal T/NK-cell lymphoma. She also had mixed findings of CAEBV that might have been attributed both to hypersensitivity to mosquito bites and to hemophagocytic lymphohistiocytosis.

Epstein Barr Virus Hepatitis: Case Series and Review

Epstein Barr virus (EBV) infection causes asymptomatic liver-associated enzyme abnormalities in 80 to 90% of cases which are often unrecognized. Patients with acute EBV infections may also develop cholestatic hepatitis with associated jaundice and hepatitis with moderate elevations in the transaminase levels. Other gastrointestinal complications associated with EBV may include splenic rupture, liver failure due to acute and/or chronic EBV infection, and perhaps, autoimmune hepatitis and hepatocellular carcinoma. This article presents a case series of EBV infections with clinically significant hepatitis and reviews the literature on the gastrointestinal complications of EBV.

EBV+ lymphoepithelial carcinoma of the parotid gland in Mexican mestizo patients with chronic autoimmune diseases

Lymphoepithelial carcinomas of the salivary gland are rare tumors constantly associated with Epstein-Barr virus (EBV) and mainly identified in Asiatic and Greenlander population. Four cases have been described in Caucasians, only two with EBV infection. We describe two cases of parotid gland lymphoepithelial carcinomas in Mexican mestizo women in which chronic latent EBV infection was documented by immunohistochemistry and in situ hybridization. One patient had primary Sjögren's syndrome and the other systemic lupus erythematosus of six and three years of evolution, respectively. Epithelial neoplastic cells showed latency pattern II (LMP1+, EBNA-2-, EBER+) with a dense inflammatory infiltrate composed mainly by CD8+ T lymphocytes. Follow-up excluded nasopharyngeal involvement in both patients. This report expands the ethnic groups in which salivary lymphoepithelial carcinomas associated with chronic latent EBV infection have been described, and illustrates for the first time its association with autoimmune diseases in two women living in a region non-endemic for this unusual neoplasm.

Genetic factors leading to chronic Epstein-Barr virus infection and nasopharyngeal carcinoma in South East China: Study design, methods and feasibility

Nasopharyngeal carcinoma (NPC) is a complex disease caused by a combination of Epstein-Barr virus chronic infection, the environment and host genes in a multi-step process of carcinogenesis. The identity of genetic factors involved in the development of chronic Epstein-Barr virus infection and NPC remains elusive, however. Here, we describe a two-phase, population-based, case-control study of Han Chinese from Guangxi province, where the NPC incidence rate rises to a high of 25-50 per 100,000 individuals. Phase I, powered to detect single gene associations, enrolled 984 subjects to determine feasibility, to develop infrastructure and logistics and to determine error rates in sample handling. A microsatellite screen of Phase I study participants, genotyped for 319 alleles from 34 microsatellites spanning an 18-megabase region of chromosome 4 (4p15.1-q12), previously implicated by a linkage analysis of familial NPC, found 14 alleles marginally associated with developing NPC or chronic immunoglobulin A production (p = 0.001-0.03). These associations lost significance after applying a correction for multiple tests. Although the present results await confirmation, the Phase II study population has tripled patient enrolment and has included environmental covariates, offering the potential to validate this and other genomic regions that influence the onset of NPC.

Chronic Epstein-Barr virus-related hepatitis in immunocompetent patients

To investigate reactivated Epstein-Barr virus (EBV) infection as a cause for chronic hepatitis. Patients with occasionally established elevated serum aminotransferases were studied. HIV, HBV and HCV-infections were excluded as well as any other immunosuppressive factors, metabolic or toxic disorders. EBV viral capsid antigen (VCA) IgG and IgM, EA-R and EA-D IgG and Epstein-Barr nuclear antigen (EBNA) were measured using IFA kits. Immunophenotyping of whole blood was performed by multicolor flow cytometry. CD8(+) T cell responses to EBV and PHA were determined according to the intracellular expression of IFN-gamma. The mean alanine aminotransferase (ALT) and gamma glutamyl transpeptidase (GGTP) values exceeded twice the upper normal limit, AST/ALT ratio < 1. Serology tests showed reactivated EBV infection in all patients. Absolute number and percentages of T, B and NK cells were within the reference ranges. Fine subset analysis, in comparison to EBV(+) healthy carriers, revealed a significant decrease of naive T cells (P < 0.001), accompanied by increased percentage of CD45RA(-) (P < 0.0001), and terminally differentiated CD28(-)CD27(-)CD8(+) T cells (P < 0.01). Moderately elevated numbers of CD38 molecules on CD8(+) T cells (P < 0.05) proposed a low viral burden. A significantly increased percentage of CD8(+) T cells expressing IFN-gamma in response to EBV and PHA stimulation was registered in patients, as compared to controls (P < 0.05). Liver biopsy specimens from 5 patients revealed nonspecific features of low-grade hepatitis. Chronic hepatitis might be a manifestation of chronic EBV infection in the lack of detectable immune deficiency; the expansion of CD28(-)CD27(-) and increase of functional EBV-specific CD8(+) T cells being the only surrogate markers of viral activity.

Atypical Hypersensitivity to Mosquito Bites without Natural Killer Cell Proliferative Disease in an Adult Patient

Hypersensitivity to mosquito bites (HMB) is a rare disorder that occurs in the first 2 decades of life and is considered to be associated with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukemia/lymphoma. EBV-encoded small nuclear RNA (EBER)-positive NK cells infiltrate the skin lesion at the site of the mosquito bite. In this report, we present the case of an adult patient with mantle cell lymphoma complicated by atypical HMB. The anti-EBV antibody titer of the patient indicated reactivation of chronic infection with this virus, and EBV DNA in the peripheral blood mononuclear cells was detected after chemotherapy by quantitative polymerase chain reaction analysis. However, an in situ hybridization analysis did not detect EBER-positive cells in the skin lesion at the bite site or in the lymph node. Peripheral NK cell lymphocytosis and EBV-associated lymphoproliferative disease did not develop. These findings suggest that some patients with chronic EBV infection may develop HMB without NK cell proliferative disease.

Epstein–Barr virus infected natural killer cell lymphoma in a patient with hypersensitivity to mosquito bite

Hypersensitivity to mosquito bite (HMB) can occur in association with chronic Epstein-Barr virus (EBV) infection and natural killer (NK) cell leukaemia/lymphoma, which was named 'Tokura-Ishihara disease'. This disease is very rare and most previous reports have been documented in Japan. We present a patient who suffered from of pustules on skin, high fever, myalgia and multiple lymph node enlargements after mosquito bite from childhood. Recently, multiple lymph nodes were palpable on his both inguinal area. Peripheral blood smear (PBS) revealed many large granular lymphocytes and the skin lesion showed a dense dermal and subcutaneous infiltrate of lymphocytes. The lymph nodes and perinodal adipose tissue were infiltrated by atypical lymphoid cells in which EBER-positive signals were identified by in situ hybridization using EBV encoded RNA-1 probe. He was diagnosed as having Tokura-Ishihara disease and receives chemotherapy now. Here, we report a case of this disease with a precise pathological description on the lymph node biopsy.

Capacity of Epstein-Barr virus to infect monocytes and inhibit their development into dendritic cells is affected by the cell type supporting virus replication.

Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that is involved in the pathogenesis of a wide spectrum of malignant and non-malignant diseases. Strong evidence implicates T lymphocytes in the control of EBV replication and tumorigenesis, but cellular components of the innate immune system are poorly characterized in terms of their function in the development of EBV-specific immunity or interaction with the virus. This study demonstrates that EBV virions produced in epithelial cells surpass their B cell-derived counterparts in the capacity to enter monocytes and inhibit their development into dendritic cells (DCs). Different ratios of the gp42 and gH glycoproteins in the envelope of virions that were derived from major histocompatibility complex class II-positive or -negative cells accounted primarily for the differences in EBV tropism. EBV is shown to enter both monocytes and DCs, although the cells are susceptible to virus-induced apoptosis only if infected at early stages of DC differentiation. The purified gH/gL heterodimer binds efficiently to monocytes and DCs, but not to B cells, suggesting that high expression levels of a putative binding partner for gH contribute to virus entry. This entry takes place despite very low or undetectable expression of CD21, the canonical EBV receptor. These results indicate that the site of virus replication, either in B cells or epithelial cells, alters EBV tropism for monocytes and DCs. This results in a change in the virus's immunomodulating capacity and may have important implications for the regulation of virus-host interactions during primary and chronic EBV infection.

In vivo transcription of the Epstein-Barr virus (EBV) BamHI-A region without associated in vivo BARF0 protein expression in multiple EBV-associated disorders.

The in vivo expression of the Epstein-Barr virus (EBV) BamHI-A rightward transcripts (BARTs) as well as the putative BART-encoded BARF0 and RK-BARF0 proteins in various EBV-associated malignancies was investigated. RT-PCRs specific for the different splice variants of the BARTs and both a nucleic acid sequence-based amplification assay and an RT-PCR specific for the BARF0 ORF were used. Abundant transcription of BARTs was found in EBV-associated Hodgkin's lymphomas, Burkitt's lymphomas (BL), T-cell non-Hodgkin's lymphomas, post-transplant lymphoproliferative disorders, AIDS-related lymphomas and gastric carcinomas. Using RNA in situ hybridization (RISH), BARTs were detected within the neoplastic cells of these malignancies. BARTs encoding RK-BARF0 were not detected. The BARTs detected were shown possibly to encode the RPMS1 and BARF0 proteins, based on their splicing. However, BARTs actually harbouring the BARF0 ORF were detected only in specimens containing a relatively large number of EBV-positive cells. New monoclonal antibodies against the BARF0 protein were generated that efficiently recognized prokaryotic and eukaryotic recombinant BARF0. However, the BARF0 protein was not detected in clinical samples, nor in EBV-positive cell lines, even though these were positive for BARTs by RISH and/or BARF0 RNA in vitro analysis. Using immunoblot analysis, no antibodies against baculovirus-expressed BARF0 protein were detected in the sera of nasopharyngeal carcinoma patients, BL patients and Hodgkin's disease patients, patients with chronic EBV infection, infectious mononucleosis patients or EBV-positive healthy donors. Thus, BARTs containing the BARF0 ORF are expressed in vivo but the BARF0 protein cannot be detected and may be expressed only marginally. It is concluded that the BARF0 protein is unlikely to play a role in vivo in EBV-positive malignancies.

Coronary Dilatation in Epstein-Barr Virus Infection

BACKGROUND: Epstein-Barr virus infection shows variety of clinical features. Chronic fashion of the disease, called chronic Epstein-Barr virus infection, and acute aggressive manifestation of the disease, Epstein-Barr virus-associated hemophagocytic syndr ome sometimes show coronary dilatation resembling that of Kawasaki disease. In this study, we demonstrated coronary arterial lesions in patients with Epstein-Barr virus infection. METHOD: Four patients with Epstein-Barr virus infection were selected in t he study. Clinical characteristics, laboratory data, and echocardiograhpic findings were studied according to the hospital records. RESULT: Patients were aged from 1 to 15 years old. The distribution of gender was three girls and one boy. Clinical diagn osis was chronic Epstein-Barr virus infection in two patients and hemophagocytic syndrome in the remains. All four patients suffered coronary arterial dilatation which were demonstrated by echocardiography. The shape of coronary artery is linear. Corona r y aneurysm like Kawasaki disease were not observed. A 15 year-old boy with chronic Epstein-Barr virus infection suffered coronary dilatation and dilated cardiomyopathy. The patient died of cardiac failure. His autopsy revealed prominent lymphocytic inf ilt ra tion in the myocardium but no inflammatory cells in coronary artery. Ten year-old girl with chronic Epstein-Barr virus infection complained chest pain and showed coronary dilatation. She died of aggressive onset of hemophagocytic syndrome. Six year-old gi rl and one year-old girl with hemophagocytic syndrome also showed coronary dilatation at the onset. One year-old girl died of interstitial pneumonia. CONCLUSIONS: Epstein-Barr virus infection sometimes shows coronary artery dilatation like Kawasak i diseas e. The echocardiographic morphology of coronary lesion is not aneurysm but dilatation in our cases. Autopsy findings did not suggest acute inflammation around coronary artery. Coronary lesions may advance silently. Once the coronary lesions obser v ed, close cardiac follow up should be held.

Epstein-Barr virus infections of the central nervous system.

Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.

Analysis of SH2D1A mutations in patients with severe Epstein-Barr virus infections, Burkitt's lymphoma, and Hodgkin's lymphoma.

Mutations or deletions in the SH2D1A (src homology 2 domain protein 1A) gene result in a severe immunodeficiency called X-linked lymphoproliferative (XLP) disease. XLP is primarily characterized by a defective immune response against the Epstein-Barr virus (EBV), resulting in an unusually severe and often fatal clinical course following EBV infection. The second major cause of death is the development of B cell lymphomas, both in EBV-infected and EBV-negative patients. To study whether the clinical manifestation of XLP gene defects and/or polymorphisms extends beyond the classically recognized phenotype, we analyzed patients for the presence of SH2D1A gene alterations who presented with fatal or nonfatal, yet unusually severe or chronic EBV infections, and other possibly EBV-associated diseases, such as Hodgkin's lymphomas or nonendemic Burkitt's lymphomas and Burkitt-type leukemias. We identified mutations of the SH2D1A gene only in the majority of patients presenting with fatal mononucleosis or an XLP family history, but not in any of the other patients studied. The only alteration determined was a polymorphism in the 5' region of the SH2D1A gene both in patient groups as well as in controls.

Hypersensitivity to mosquito bites as the primary clinical manifestation of a juvenile type of Epstein-Barr virus-associated natural killer cell leukemia/lymphoma

Hypersensitivity to mosquito bites or mosquito allergy is a mysterious disorder that has been reported mainly in Japanese patients (at least 58 patients) in the first two decades of life. The skin lesion at bite sites is typically a bulla that develops into necrosis. Patients simultaneously exhibit a high temperature and general malaise and subsequently may experience lymphadenopathy and hepatosplenomegaly. Recent studies have revealed that this mosquito hypersensitivity is associated with chronic Epstein-Barr virus infection and natural killer cell leukemia/lymphoma. The natural killer cell, infected with monoclonal (or oligoclonal) Epstein-Barr virus, seems to be involved in the pathogenesis of the hypersensitivity. Half of the patients reported died of hemophagocytic syndrome (or malignant histiocytosis), granular lymphocyte proliferative disorder, or lymphomas. We propose that this disease, defined as the triad of hypersensitivity to mosquito bites, chronic Epstein-Barr virus infection, and natural killer cell leukemia/lymphoma, is a clinical entity mostly seen in Asians. (J Am Acad Dermatol 2001;45:569-78.)

No BCL-2 protein over expression but BCL-2/IgH rearrangements in B cells of patients with persistent polyclonal B-cell lymphocytosis.

Persistent polyclonal B-cell lymphocytosis is a rare hematological disorder, characterized by a chronic, stable and absolute polyclonal lymphocytosis, the presence of binucleated lymphocytes, a polyclonal increase in serum IgM immunoglobulin and clonal cytogenetic abnormalities involving chromosome 3. For explaining the expansion of B-lymphocytes pool in PPBL, an association with cigarette smoking and/or chronic Epstein-Barr virus infection have been suggested but both hypotheses have been ruled out. We studied the presence of BCL-2/IgH rearrangements in a series of eight PPBL patients (seven females and one male) by a nested polymerase chain reaction (PCR), targeting the Major Breakpoint Region in BCL-2 locus and we explored the BCL-2 protein expression by Western blot. We demonstrated: (a) the constant presence of BCL-2/IgH rearrangements in eight out of eight DNA samples, (b) multiple rearrangements in three out of eight cases and, (c) normal BCL-2 protein expression, as compared to BCL-2 level in B-lymphocytes from healthy population. Despite the presence of BCL-2/IgH rearrangements, the accumulation of B lymphocytes in PPBL is not related to an overexpression of BCL-2 protein.